Abstract
We previously reported that the levels of α-syn oligomers, which play pivotal pathogenic roles in age-related Parkinson's disease (PD) and dementia with Lewy bodies, increase heterogeneously in the aging brain. Here, we show that exogenous α-syn incubated with brain extracts from older cynomolgus monkeys and in Lewy body pathology (LBP)-susceptible brain regions (striatum and hippocampus) forms higher amounts of phosphorylated and oligomeric α-syn than that in extracts from younger monkeys and LBP-insusceptible brain regions (cerebellum and occipital cortex). The increased α-syn phosphorylation and oligomerization in the brain extracts from older monkeys and in LBP-susceptible brain regions were associated with higher levels of polo-like kinase 2 (PLK2), an enzyme promoting α-syn phosphorylation, and lower activity of protein phosphatase 2A (PP2A), an enzyme inhibiting α-syn phosphorylation, in these brain extracts. Further, the extent of the age- and brain-dependent increase in α-syn phosphorylation and oligomerization was reduced by inhibition of PLK2 and activation of PP2A. Inversely, phosphorylated α-syn oligomers reduced the activity of PP2A and showed potent cytotoxicity. In addition, the activity of GCase and the levels of ceramide, a product of GCase shown to activate PP2A, were lower in brain extracts from older monkeys and in LBP-susceptible brain regions. Our results suggest a role for altered intrinsic metabolic enzymes in age- and brain region-dependent α-syn oligomerization in aging brains.
Highlights
Aging is the most important risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [1, 2], which are pathologically characterized by the formation of fibrous protein inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs), i.e. Lewy body pathology (LBP) [3, 4]
We examined α-syn oligomerization and phosphorylation by incubating recombinant human α-syn in extracts isolated from brain regions relatively susceptible to LBP and those relatively insusceptible to LBP [3, 4, 39] of cynomolgus monkeys of varying age
To find the minimal antibody concentration needed for complete depletion of the endogenous α-syn, brain extracts from the striatum and hippocampus with a protein concentration of 1 mg/ml were incubated with different concentrations of the antiα-syn antibody conjugated to Protein G for 24 h at 37 °C
Summary
Aging is the most important risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [1, 2], which are pathologically characterized by the formation of fibrous protein inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs), i.e. Lewy body pathology (LBP) [3, 4]. Α-syn in LBs and LNs is fibrotic, increasing evidence suggests that it is the small α-syn aggregates (oligomers and protofibrils) rather than the α-syn fibrils that are toxic to neurons [7,8,9,10]. We previously reported that aging in the brain is associated with an increase in α-syn oligomers, with the effect differing between certain brain regions [18]. The intrinsic factors that lead to the age- and brain region-dependent accumulation of α-syn oligomers remains elusive. None of the previous studies have investigated how PLK2 and PP2A change in the aging brain and whether their changes are associated with the age- and brain region-dependent α-syn oligomerization
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